Nanoparticle-mediated delivery of anti-PU.1 siRNA via localized intracisternal administration reduces neuroinflammation
Open accessAbstract
Neuroinflammation is a hallmark of neurodegenerative disorders including Alzheimer's disease (AD). Microglia, the brain's immune cells, express many of the AD-risk loci identified in genome wide association studies and present a promising target for anti-inflammatory RNA therapeutics but are difficult to transfect with current methods. Here, several lipid nanoparticle (LNP) formulations are examined, and a lead candidate that supports efficient RNA delivery in cultures of human stem cell-derived microglia-like cells (iMGLs) and animal models of neuroinflammation is identified. The lead microglia LNP (MG-LNP) formulation shows minimal toxicity and improves delivery efficiency to inflammatory iMGLs, suggesting a preference for delivery into activated microglia. Intraperitoneal injection of the MG-LNP formulation generates widespread expression of the delivered reporter construct in all organs, whereas local intracisternal injection directly into the cerebrospinal fluid leads to preferential expression in the brain. It is shown that LNP-mediated delivery of siRNA targeting the PU.1 transcription factor, a known AD-risk locus, successfully reduces PU.1 levels in iMGLs and reduces neuroinflammation in mice injected with LPS and in CK-p25 mice that mimic the chronic neuroinflammation seen in AD patients. The LNP formulation represents an effective RNA delivery vehicle when applied intrathecally and can be broadly utilized to test potential neuroinflammation-directed gene therapies.
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Microglia are notoriously refractory to gene silencing.
“Microglia are notoriously refractory to gene silencing, highlighting the significance of this result [31].”
From Elucidating brain transport pathways and cell type-dependent gene silencing of a durable lipid–siRNA conjugate administered into cerebrospinal fluid (2025) · cites this paper as [31]
Microglia are notoriously refractory to gene silencing.
“Microglia are notoriously refractory to gene silencing, highlighting the significance of this result.38”
From Lipid-siRNA conjugate accesses a perivascular transport mechanism and achieves widespread and durable knockdown in the central nervous system (2024) · cites this paper as [38]
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- Authors
- Ralvenius, W. T., Andresen, J. L., Huston, M. M., Penney, J., Bonner, J. M., Fenton, O. S., Langer, R., & Tsai, L.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- Massachusetts Institute of Technology (US)
- University of North Carolina at Chapel Hill (US)
- Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology Cambridge MA 02139 USA
- Broad Institute (US)
- Corresponding author
- Fenton, Owen S.
- Tsai, Li‐Huei
- ORCID
- Venue
- Advanced Materials
- Publisher
- Wiley
- Published
- 2023-12-08
- Volume
- 36
- Issue
- 8
- Pages
- e2309225-e2309225
- ISSN
- 0935-9648 (ISSN-L)
- 1521-4095
- OpenAlex
- W4389136694
- Cited by
- 78
- References
- 28
- Citations by year
- 2026: 27 · 2025: 34 · 2024: 17
- FWCI
- 6.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Advanced Materials (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (177920, 171909)
- Alzheimer's Association (AARF‐19‐616816)
- JPB Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- neuroinflammation, Alzheimer's disease, PU.1, siRNA delivery, lipid nanoparticles, intracisternal injection, intrathecal drug delivery, microglia, RNA therapeutics, LPS-induced neuroinflammation, gene therapy
- MeSH terms
- Neuroinflammatory Diseases, Alzheimer Disease, Animals, Humans, RNA, Small Interfering, Mice, Nanoparticles, Genome-Wide Association Study
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